1. Field of the Invention
The present invention relates to an automatic sample pretreatment device of an automatic analysis apparatus for a specific component in a sample. The automatic sample pretreatment device is preferably integrated into the automatic analysis apparatus, and serves to dilute a sample and/or to cause a pretreatment reaction automatically prior to the measurement. Particularly, the present invention relates to an automatic pretreatment device for dilution or pretreatment reaction of a sample, integrated into a biochemical analysis apparatus such as an automatic immunoassay apparatus.
2. Description of the Related Art
Clinical diagnosis of some specific diseases is conducted by measurement of a specific substance in a body fluid such as blood. For example, immunoassay with an antibody for a specific substance, which can be conducted readily with relatively high sensitivity, is widely employed in clinical test nowadays.
In biochemical or immunological measurement, the sample is usually pretreated, prior to the measurement, for dilution of the sample containing a high concentration of the objective substance to bring the concentration to the analysis range of the measurement apparatus, or pretreated for improvement of measurement sensitivity or measurement precision by canceling the influence of a coexisting substance in the sample or activating the objective component. The reaction for the pretreatment includes heating treatment of the sample to denature protein in the sample or to inactivate or activate a specific component; and addition of a pretreatment reagent other than the measurement reagent. More specifically, in immunoassay of a protein-bonded low molecular component in a sample, the protein is denatured preliminarily by application of heat, or addition of an acid or alkali to dissociate the low molecular component from the protein, and subsequently the immunoassay is conducted.
As described above, the pretreatment including dilution, and pretreatment reaction including addition of a denaturing reagent, agitation, incubation, and addition of an neutralizing agent is conducted manually in most cases by taking a long time. Therefore, measurement of a large number of samples is time-consuming, troublesome, and less reproducible, disadvantageously.
Various methods are proposed to solve the above problems. In one method, a pretreatment reaction apparatus is provided separately. In another method, a sample and a pretreating reagent are allowed to react in a reaction cuvette of an automatic analysis apparatus, and subsequently a measurement reagent is added thereto to conduct measurement. By such a method, the pretreatment operation can be simplified, and the measurement reproducibility can be improved. However, the use of a separate pretreatment reaction device requires transfer of the sample to the measurement apparatus after the pretreatment reaction, producing another problem that the entire operation from the pretreatment to the measurement cannot be automated.
The above second method, in which a sample and a pretreatment reagent are introduced into a reaction cuvette of an automatic analysis apparatus to cause a pretreatment reaction, involves the problem that the practicable pretreatment reactions are limited. Further, in this method, the reaction cuvette for the pretreatment reaction is usually replaced with a new one and is discarded after the pretreatment reaction of each sample in order to prevent contamination by other samples. Therefore, when plural kinds of measurement are conducted with the one pretreatment reaction product, the pretreatment reaction should be repeated for each of the measurements, requiring a lager amount of the sample, or requiring longer time for the pretreatment, disadvantageously.
A sample which contains the objective substance of the measurement at a concentration exceeding the scale range of the measurement apparatus should be diluted before the measurement. In this case, the non-diluted sample is firstly subjected to measurement, then the sample is diluted manually or by use of a dilution device, and the diluted sample is subjected again to the measurement. The concentration is calculated by multiplying the measured value by the dilution factor. Otherwise, non-diluted samples are successively measured, and samples falling outside the measurable concentration range are diluted in an off-line process of the measurement apparatus and are measured again by inputting the dilution factor. Alternatively, samples found to be outside the measurable range are diluted on-line during the measurement to obtain the concentration by multiplication of the inputted dilution factor.
However, the dilution including manual dilution, and automatic dilution by an off-line process by the measurement apparatus requires operations of sample dilution, sample resetting, apparatus operation condition setting, and so forth, which cannot be automated, and requires longer time for measurement. Furthermore, with automatic preliminary on-line dilution by an analysis apparatus, although the dilution is conducted automatically and the measurement time is shortened, the measurement speed is still low disadvantageously.
It was considered by the inventors of the present invention that the above problems encountered in the prior art are caused by the practice of the pretreatment (including a pretreatment reaction and dilution) and measurement in the same measurement vessel in a measurement reaction system. For example, a measurement apparatus equipped with an automatic on-line dilution device comprises a pretreatment vessel for dilution or the like and a measurement incubator for immune reaction, enzyme reaction or the like in integration, and uses one cuvette for each measurement item for each sample. Such an apparatus requires repetition of the same dilution for each of plural measurements for one and the same sample.
Therefore, comprehensive studies have been made on an efficient automatic pretreatment device for dilution, pretreatment reaction, and other pretreatment.